CHART 1. COXs Med ia ted Ar a ch id on ic Acid
Ca sca d e
F ir st En a n tioselective Tota l Syn th esis of
(8S,12R,15S)-P r osta gla n d in J 2
Giuseppe Zanoni,* Alessio Porta, Quintino De Toma,
Francesca Castronovo, and Giovanni Vidari*
Dipartimento di Chimica Organica, Universita` di Pavia,
Via Taramelli 10, 27100 Pavia, Italy
gzanoni@unipv.it
Received April 18, 2003
Abstr a ct: Enantioselective synthesis of natural PGJ 2 has
been accomplished for the first time starting from the
commercially available enantiopure aldehyde 7 in 10%
overall yield. The key reaction was a novel prostaglandin
class interconversion, i.e., an allylic 1,3-transposition across
alcohol 9 derived from compound 14 in 73% overall yield.
In principle, the unnatural enantiomer of PGJ 2 could be
obtained starting from the commercially available enan-
tiopure monobenzoate 7a following our strategy.
CHART 2
Prostaglandin J 2 (PGJ 2) 1 was first reported in 1976
by Colton and Chinn in a study aimed at finding new
postaglandin derivatives endowed with antispasmodic
activity.1 Some years later, Fukushima and Willis dis-
covered that cyclopentenone PGJ 2 is also formed in vivo
by dehydration within the cyclopentenone ring of the
endogenous prostaglandin PGD2 2 (Chart 1).2 The same
reaction has been reproduced in vitro.
As a consequence of these intracellular events, i.e., the
COXs (COX-1 and COX-2)-mediated arachidonic acid
cascade, PGJ 2 was initially named 9-deoxy-∆9-PGD2.3
PGJ 2 is further metabolized to ∆12-PGJ 2 3 and then to
15-deoxy-∆12,14-PGJ 2 4 in a nonenzymatic fashion. Cy-
clopentenone prostaglandins of the J 2 series have their
own unique spectrum of biological effects, including
antitumor, antiinflammatory, and antiviral activities.
In addition, they are reported to inhibit cell cycle
progression, to suppress viral replication, and to stimu-
late osteogenesis, apoptosis, and the expression of stress-
related genes in various cell types including human
breast cancer cells.4
based on (i) acid-mediated dehydration of the correspond-
ing PGD2 2,6 (ii) SiO2-mediated rearrangement of pros-
taglandin-lactone 5,7 and (iii) hydrazine mediated rear-
rangement of epoxy-PGA2 derivative 61 (Chart 2).
To explore the role of enantioselectivity in the biological
activities of PGJ 2, an asymmetric synthesis of both
enantiomers of prostaglandin J 2 is therefore highly
desirable. In this paper, we describe the first enantiose-
lective route to natural (+)-(8S,12R,15S)-prostaglandin
J 2 1, which could be applied for the preparation of the
(-)-(8R,12S,15R) enantiomer.
Despite the burgeoning new biological activities as-
sociated with PGJ 2, surprisingly its enantioselective total
synthesis is still waiting to be accomplished. Besides the
total synthesis of (()-PGJ 2 reported by Roberts and
Newton,5 the other published racemic approaches are
(1) Colton, F. B.; Chinn, L. J . U.S. Patent 3 954 844, 1976.
(2) (a) Fukushima, M.; Kato, T.; Ota, K.; Narumiya, S. Biochem.
Biophys. Res. Commun. 1982, 109, 626-633. (b) Mahmud, I.; Smith,
D. L.; Whyte, M. A.; Nelson, J . T.; Cho, D. Tokes, Alvarez, L. G.; Willis,
A. L. Prostaglandins Leukotrienes Med. 1984, 16, 131-146.
(3) Nosjean, O.; Boutin, J . A. Cell. Signaling 2002, 14, 573-583.
(4) (a) Kliewer, S. A.; Lenhart, J . M.; Willson T. M.; Patel, I.;
Lehmann, J . M. Cell 1995, 83, 813-819. (b) Straus, D. S.; Glass, C. K.
Med. Res. Rev. 2001, 21, 185-210 and references therein. (c) Negishi,
M.; Katoh, H. Prostaglandins Other Lipid Mediators 2002, 68-69,
611-617.
Our synthetic strategy, illustrated in Scheme 1, takes
advantage of two important synthetic bonuses: (i) the
commercial availability of multigram amounts of either
(6) Morton, D. R., J r. U.S. Patent 4 016 184, 1977.
(5) (a) Ali, S. M.; Chapleo, B. C.; Finch, M. A. W.; Roberts, S. M.;
Wooley, G. T.; Cave, R. C.; Newton, R. F. J . Chem. Soc., Perkin Trans.
1 1980, 2093-2097. (b) Ali, M. S.; Finch, M. A. W.; Roberts, S. M.;
Newton, R. F. J . Chem. Soc., Chem. Commun. 1979, 679-682.
(7) Bundy, G. L.; Morton, D. R.; Peterson, D. C.; Nishizawa, E. E.;
Miller, W. L. J . Med. Chem. 1983, 6, 790-799. The racemic modifica-
tion of PGJ 2 was obtained by these authors; see ref 3 in: Suzuki, M.;
Yanagisawa, A.; Noyori, R. Tetrahedron Lett. 1984, 25, 1383-1386.
10.1021/jo034502h CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/03/2003
J . Org. Chem. 2003, 68, 6437-6439
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